Twenty-four patients with unstable angina pectoris, defined as chest pain at rest with transient ST segment deviation of at least 1 mm, were randomly assigned to blinded treatment with either placebo or intravenous recombinant human tissue-type plasminogen activator (rt-PA). Before randomization, all patients were treated with oral beta-blockers, calcium antagonists, nitrates, and continuous intravenous heparin for a monitoring period of 12 to 28 hr. After this monitoring period the 24 patients were randomly assigned to receive either placebo or 1.75 mg/kg intravenous rt-PA given over 12 hr at a rate of 0.75 mg/kg over 1 hr, 0.5 mg/kg over 4 hr, and 0.5 mg/kg over 7 hr. One patient, assigned to receive placebo, developed acute myocardial infarction after randomization but before receiving the study drug. Ischemic events were recorded during a hospital follow-up period of at least 4 days unless a further intervention was indicated or the coronary angiogram was normal. The follow-up period was 7 +/- 5 days (mean +/- SD) after the placebo infusion and 8 +/- 4 days after the infusion of rt-PA. Unstable angina pectoris persisted after the completion of the infusion in six of 11 patients receiving placebo and only one of 12 patients receiving rt-PA (p less than .03). Coronary angiography, performed 38 +/- 19 hr after the infusion, demonstrated subocclusive thrombus in eight of 11 patients receiving placebo but in none of 11 patients treated with rt-PA (p less than .002). One patient on rt-PA refused coronary angiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies in patients with congestive heart failure (CHF) have demonstrated an abnormal beta-adrenergic reflex vasodilation during orthostatic tilt. Baroreflex modulation of vascular resistance in patients with CHF was investigated during therapy with a vasoselective calcium antagonist, felodipine. Eight patients on conventional therapy for severe CHF were studied after a 3 week course of additional felodipine or placebo treatment under randomized, double-blind, and crossover conditions. Forearm subcutaneous vascular resistance (FSVR) was estimated with use of the local 133Xe washout. Aortic pulsatile stretch, expressed as the systolic distension in percent of diastolic diameter, was calculated from echocardiographic measurements of aortic root diameters. At 3 weeks, felodipine reduced the arterial pressure, systemic vascular resistance, and FSVR, preserved cardiac filling pressures and heart rate, and increased cardiac output, stroke volume, and aortic pulsatile stretch. Upright tilt (45 degrees) was used to study baroreflex-mediated cardiovascular responses. The unloading of cardiopulmonary baroreceptors during upright tilt was substantial and about equal during both treatment courses, but the pulse pressure was maintained during the placebo and decreased during the felodipine period. During tilt, the patients on placebo failed to increase heart rate and their FSVR, systemic vascular resistance, and arterial mean pressure were decreased, whereas during tilt after felodipine, heart rate and systemic vascular resistance increased to maintain arterial mean pressure and FSVR also tended to increase. Both the stroke volume and aortic pulsatile stretch increased during tilt in patients on placebo but they decreased in those on felodipine. The tilt caused increments in circulating norepinephrine and epinephrine levels during both treatment regimens. Regulation of FSVR during the sympathetic stimulation of orthostatic stress was further elucidated. Proximal neural blockade caused an increase in FSVR during tilt in patients on placebo and a decrease in FSVR during tilt in those on felodipine. Local beta-adrenoceptor blockade caused similar increments in FSVR during tilt in patients on both treatments. Combined proximal and local blockade still increased FSVR during tilt in those on placebo, but caused no change in FSVR during tilt in those on felodipine. This study demonstrates that felodipine normalizes baroreflex control of vascular resistance in patients with CHF.(ABSTRACT TRUNCATED AT 250 WORDS)

The Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure was designed to determine whether vasodilator drugs could alter the survival of patients with chronic congestive heart failure treated with digoxin and diuretics. Among the 642 patients entered into the study, 273 were randomly assigned to placebo, 186 were randomly assigned to the combination of hydralazine and isosorbide dinitrate, and 183 patients were randomly assigned to prazosin; all patients were followed for periods ranging from 6 months to 5.7 years. Treatment with hydralazine-nitrate produced a 28% reduction in mortality compared with that in patients receiving placebo (95% confidence interval, 3% to 46%), whereas prazosin exerted no apparent beneficial effect. Data were further examined to determine if any baseline variables had an impact on the response to treatment. Mortality in the placebo group was higher in those with coronary artery disease, with a history of antiarrhythmic drug use, and with values lower than the median for ejection fraction and exercise tolerance. A reduction in mortality with hydralazine-isosorbide dinitrate was observed in all of the above pairs of subgroups as well as in those above and below 60 years of age and those with and without a history of hypertension or excess alcohol ingestion. The benefit of hydralazine and isosorbide dinitrate was particularly prominent in younger patients with a lower ejection fraction and those with a history of hypertension and without an alcoholic history.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether prophylactic antiarrhythmic therapy influences mortality in high-risk patients after acute myocardial infarction, 143 such patients were randomized in a double-blind individually dose-adjusted, placebo-controlled trial an average of 14 +/- 7 days after myocardial infarction and followed for 1 year. Patients were judged to be at high risk on the basis of (1) ejection fraction less than 40% (n = 60), (2) arrhythmias of Lown class 3 or higher (n = 26), or (3) both (n = 57). Aprindine was chosen because of its long half-life, few side effects, and antiarrhythmic efficacy. Baseline characteristics in the treatment arms did not differ. Holter-detected arrhythmias were reduced in aprindine-treated patients at 3 months (p less than .001) and at 1 year (p less than .001). One patient was lost to follow-up; in the remaining patients 1 year mortality was 20% (28/142; 12 aprindine and 16 placebo). There was no significant difference between the two study arms in overall mortality and sudden death. However, among those who died, median duration of survival was longer in aprindine-treated patients (86 vs 21.5 days) (p = .04). Although antiarrhythmic treatment with aprindine of high-risk patients after myocardial infarction does not affect 1 year survival, mortality appears to be delayed; thus there may be a role for short-term treatment before more definitive therapy such as surgery.

In Phase I of the NHLBI trial of Thrombolysis in Myocardial Infarction (TIMI), 290 patients admitted within 7 hr after onset of acute infarction were randomly assigned to intravenous treatment with either streptokinase (SK) or recombinant tissue-type plasminogen activator (rt-PA). Left ventricular function was measured from contrast ventriculograms in 145 patients with both pretreatment and predischarge studies analyzable. Regional wall motion in the infarct site was measured by the centerline method and expressed in units of standard deviations (SDs) from the mean motion in 52 normal subjects. Patients treated with rt-PA (n = 77) achieved a significantly higher reperfusion rate after 90 min of treatment. Perfusion of the infarct-related artery improved from visual grade 0 or 1 (total occlusion or penetration without perfusion) to grade 2 or 3 (partial or full reperfusion) in 62% receiving rt-PA vs 31% receiving SK (n = 68) (p less than .001). However, the ejection fraction did not change significantly from before treatment to before discharge in either treatment group (+0.7 +/- 6.7% vs +1.0 +/- 8.3%, respectively). A small but significant increase in regional wall motion was observed in each of the two groups (+0.4 +/- 0.8 vs +0.3 +/- 0.8 SD/chord, respectively; each p less than .001 compared with baseline). This was countered by declines in the hyperkinesis of the noninfarct region (-0.3 +/- 1.0 SD/chord [p = .01] compared with baseline and -0.2 +/- 1.0 SD/chord [p = .23], respectively). Analysis of the combined groups revealed that the ejection fraction increased only in patients who achieved reperfusion by 90 min after onset of therapy or who had subtotal occlusions initially. There was greater recovery of left ventricular function in patients who achieved reperfusion earlier vs later than 4 hr after symptom onset and in patients with vs without some collateral circulation to the infarct-related artery.

To determine the role of tissue-type plasminogen activator (t-PA) and immediate percutaneous transluminal coronary angioplasty (PTCA) in treating patients with evolving transmural myocardial infarction, 50 patients received t-PA (1.25 mg/kg iv over 3 hrs) or placebo according to 3:1 double-blind randomization 3.8 +/- 1.1 hr after onset of symptoms. At emergency coronary arteriography, patency of the infarct-related vessel was demonstrated in 32 of 38 (84%) patients receiving t-PA vs two of 12 (17%) receiving placebo (p less than .001). Of the 32 patients with recanalization after t-PA, 28 had a residual stenosis of at least 50% and underwent randomization a second time to immediate (n = 15) or no PTCA (n = 13). Immediate PTCA of the infarct-related vessel was successful in all 15 patients, with reduction of the residual diameter stenosis from 80.8 +/- 8.2% to 32.5 +/- 15.6% (p less than .001). The incidence of postinfarction angina (greater than or equal to 20 min of chest discomfort and reversible electrocardiographic changes) and reinfarction (documented by recurrent creatine kinase isoenzyme elevation) was reduced in the patients receiving t-PA and PTCA (2/15) compared with that in patients receiving t-PA alone (7/13; p = .006). At 1 week there was no difference in patency of the infarct-related vessel (12/15 t-PA and PTCA vs 9/13 t-PA only) or in global ventricular functional change between the two groups (0.5 +/- 10.4 SD/chord for t-PA and PTCA vs -2.1 +/- 8.2 SD/chord for t-PA only).(ABSTRACT TRUNCATED AT 250 WORDS)

In this study, sequential cardiopulmonary exercise testing was used to assess the physiologic benefits of a single-chamber ventricular pacing system that utilizes a piezoceramic sensor to adjust heart rate by detecting "physical activity." An initial exercise test was conducted with the pacemaker programmed (based on a randomization table) to either the fixed rate (VVI, 70 beats/min) or rate-variable (VVI-Act) mode, and the results were compared with those obtained during a second exercise test in which the pacemaker was programmed to the alternate pacing mode. A 1.5 to 2 hr rest period was permitted between exercise tests, each of which consisted of a symptom-limited constant speed (3.0 mph) Balke protocol with 2 min stages commencing at 0.0% grade with increments of 2.5% at end of each stage. Compared with findings during fixed-rate VVI pacing, VVI-Act pacing was associated with greater exercise-induced positive chronotropic response (mean maximum heart rate VVI-Act 128 +/- 15.3 beats/min vs VVI 90 +/- 28.4 beats/min; p less than .01), prolongation of exercise duration (VVI-Act 10.2 +/- 3.8 min vs VVI 7.7 +/- 2.5 min; p less than .01), increased peak oxygen consumption (VVI-Act 1617 +/- 656 ml O2/min vs VVI 1325 +/- 451 ml O2/min; p less than .01), and onset of anaerobic threshold at a higher oxygen consumption (VVI-Act 1208 +/- 343 ml O2/min vs VVI 1064 +/- 377 ml O2/min: p less than .01). Additionally, of 44 comparable exercise stages tested in the two pacing modes, perceived exertion (assessed by a numerical grading system) was lower in 38 of 44 instances during VVI-Act compared with VVI pacing.(ABSTRACT TRUNCATED AT 250 WORDS)

To examine whether early intervention with timolol influences the occurrence of left ventricular thrombi in acute anterior myocardial infarction, 40 patients with acute anterior myocardial infarction admitted to hospital within 6 hr of onset of symptoms were randomly assigned to receive intravenous followed by oral timolol maleate or placebo. Five (25%) of 20 patients in the placebo group and 14 (73.7%) of 19 patients with confirmed infarction in the timolol group developed a left ventricular apical thrombus as detected by two-dimensional echocardiography from 2 to 10 days after inclusion (p less than .005). Patients received anticoagulants only after a left ventricular thrombus had been diagnosed. Only one patient with thrombus suffered peripheral embolization (timolol group). The treatment groups were comparable with respect to location of regional left ventricular dysfunction, electrocardiographic changes, and infarct size estimated by creatine kinase release. However, computer-assisted regional wall motion analysis demonstrated significantly reduced apical wall motion in the timolol group compared with the placebo group (p less than .01). Also, the mean heart rate during the first 10 days after the acute infarction was reduced by 13% in the timolol group (p less than .001). The reduction in heart rate and left ventricular apical wall motion caused by timolol in patients with acute anterior myocardial infarction may increase the occurrence of left ventricular thrombi.

Among the side effects commonly reported with the use of beta-blockers are symptoms related to the central nervous system (CNS). In this study we compared the effects of four beta-blockers with different ancillary properties (atenolol, metoprolol, propranolol, and pindolol) and placebo on objective and subjective measures of CNS function in 30 healthy male subjects. All subjects were randomly assigned to a double-blind, placebo controlled, Latin-square design study in which five 1 week periods of drug or placebo administration were separated by 2 week washout periods. Laboratory evaluations were conducted at the end of each treatment period, and included multistage exercise stress testing; questionnaire assessments of mood state, sexual function, and sleep habits; tests of psychomotor function; and overnight polysomnographic measures of sleep. Significant effects on sleep continuity were observed for each of the lipophilic drugs, as reflected in the number of awakenings (pindolol = 6.4 +/- 5.0; propranolol = 6.3 +/- 3.2; metoprolol = 7.2 +/- 4.7; atenolol = 3.6 +/- 2.9; placebo = 3.9 +/- 2.7) and time of wakefulness (pindolol = 20.6 +/- 27.0 min; propranolol = 15.5 +/- 23.0 min; metoprolol = 19.5 +/- 24.3 min; atenolol = 10.2 +/- 11.6 min; placebo = 9.2 +/- 74.5 min). Only pindolol significantly affected rapid eye movement (REM) sleep time (pindolol = 54.5 +/- 21.9 min; placebo = 74.5 +/- 74.5 min) and REM latency (pindolol = 175.0 +/- 60.7 min; placebo = 95.4 +/- 43.8 min). Subjective reports of sleep similarly indicated increased wakefulness and greater restlessness with lipophilic beta-blockers.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of thrombolysis in acute myocardial infarction on enzymatic infarct size, left ventricular function, and early mortality was studied in subsets of patients in a randomized trial. Early thrombolytic therapy with intracoronary streptokinase (152 patients) or with intracoronary streptokinase preceded by intravenous streptokinase (117 patients) was compared with conventional treatment (264 patients). All 533 patients were admitted to the coronary care unit within 4 hr after onset of symptoms indicative of acute myocardial infarction. Four hundred eighty-eight patients were eligible for this detailed analysis, and 245 of these were allocated to thrombolytic therapy and 243 to conventional treatment. Early angiographic examinations were performed in 212 patients allocated to thrombolytic therapy. Patency of the infarct-related artery was achieved in 181 patients (85%). Enzymatic infarct size, as measured from cumulative alpha-hydroxybutyrate dehydrogenase release, was smaller in patients allocated to thrombolytic therapy (median 760 vs 1170 U/liter in control patients, p = .0001). Left ventricular ejection fraction measured by radionuclide angiography before discharge from the hospital was higher after thrombolytic therapy (median 50% vs 43% in control patients, p = .0001). Three month mortality was lower in patients allocated to thrombolytic therapy (6% vs 14% in the control group, p = .006). With the use of multivariate regression analysis, infarct size limitation, improvement in left ventricular ejection fraction, and three month mortality were predicted by sum of the ST segment elevation, time from onset of symptoms to admission, and Killip class at admission. Thrombolysis was most effective in patients admitted within 2 hr after onset of symptoms and in patients with a sum of ST segment elevation of 1.2 mV or more. On the other hand, no beneficial effects of streptokinase on enzymatic infarct size, left ventricular function, or mortality were observed in the subset of patients with a sum of ST segment elevation of less than 1.2 mV who were admitted between 2 and 4 hr after onset of symptoms.

Although current methods of myocardial preservation for coronary bypass surgery provide excellent protection, perioperative ischemic injury persists. Platelet activation and myocardial deposition may contribute to perioperative ischemic injury and early postoperative graft occlusion. Dipyridamole may reduce platelet activation and myocardial deposition and reduce perioperative ischemic injury. A prospective randomized trial was instituted in 40 patients undergoing elective coronary bypass surgery to evaluate the effects of dipyridamole on myocardial platelet and leukocyte deposition and the cardiac release of thromboxane and prostacyclin. Twenty patients received intravenous dipyridamole (0.24 mg/kg/hr) beginning 20 hr before surgery and continuing for 24 hr after surgery. Autologous platelets, leukocytes, and erythrocytes were labeled with 111In, 99mTc, and 51Cr, respectively, and were infused before release of the cross-clamp. Myocardial biopsy samples were obtained 10, 20, and 30 min after aortic declamping and indicated that platelets and leukocytes were deposited in the myocardium during reperfusion. Dipyridamole reduced both platelet (with dipyridamole 1540 +/- 2100 cells/mg, no dipyridamole 14,500 +/- 33,000 cells/mg) and leukocyte deposition (with dipyridamole 16 +/- 32 cells/mg, no dipyridamole 63 +/- 110 cells/mg). Cardiac release of thromboxane B2 (the stable metabolite of thromboxane A2) occurred in the early postoperative period and was reduced by dipyridamole (with dipyridamole 0.039 +/- 0.16 mg/liter, no dipyridamole 0.27 +/- 0.18 micrograms/liter, p less than .05). Dipyridamole reduced cardiac platelet deposition and thromboxane release and may reduce perioperative ischemic injury and early graft occlusion.

Myocardial injury was assessed with the use of enzyme indexes in 40 patients randomly assigned to one of two groups undergoing coronary artery bypass surgery. Twenty patients received cold cardioplegia delivered by retrograde coronary sinus perfusion and 20 received cardioplegic solution by anterograde aortic root perfusion. Creatine kinase isoenzyme MB and lactate dehydrogenese isoenzyme 1 and isoenzyme 2 assays were carried out on blood samples obtained from the coronary sinus before aortic cross-clamping and 0, 5, and 30 min after aortic unclamping. Levels of these enzymes were also obtained from venous blood samples before aortic cross-clamping and 3, 8, 14, and 20 hr after aortic unclamping and 2, 3, 4, and 5 days after surgery. Preoperative and postoperative hemodynamic measurements (Swan-Ganz catheter) and radionuclide wall motion studies were also obtained for comparison. There was no overall significant difference between the two groups postoperatively in terms of enzyme indexes, hemodynamic measurements, or results of wall motion studies. We conclude that retrograde coronary sinus perfusion is an alternative to aortic root perfusion in delivering cold cardioplegia. More studies are required to determine which subgroup of patients with coronary artery disease may benefit from retrograde coronary perfusion.

Induction of rapid ventricular tachycardia or fibrillation during therapy with amiodarone is associated with an increased risk of sudden death. To determine whether the addition of a type IA antiarrhythmic agent to therapy would improve outcome, 37 patients in whom ventricular tachyarrhythmia of a cycle length less than 350 msec was induced after 14 +/- 2 days of amiodarone were randomly assigned to therapy with amiodarone alone (group 1, 20 patients) or amiodarone plus type IA agent (group 2, 17 patients). Type IA therapy consisted of procainamide in 13 patients and quinidine in four procainamide-intolerant patients. To assess the short-term effects of a type IA agent on inducibility of ventricular tachyarrhythmia, cycle length, and hemodynamic tolerance, 16 of 20 patients in group 1 and all patients in group 2 underwent repeat programmed stimulation after the intravenous administration of procainamide during amiodarone therapy (mean procainamide serum concentration 7.2 +/- 2.0 micrograms/ml). Procainamide prevented induction of sustained arrhythmia in only two of 33 patients. Procainamide increased the cycle length of induced ventricular tachycardia from 283 +/- 30 to 352 +/- 46 msec (p less than .001). After the addition of procainamide, 16 of 31 patients vs 10 of 37 patients on amiodarone alone had an induced arrhythmia that was tolerated hemodynamically (p less than .05). There were no differences between groups 1 and 2 with respect to patient or arrhythmia characteristics, response to short-term procainamide, or duration of follow-up. The mean follow-up for all patients was 14 +/- 10 months.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been postulated that platelet function plays an important role in the initiation of atherosclerosis. Currently there are no definitive data on the longer-term effects of regular physical exercise on platelet function in humans. We assessed the influence of regular moderate-intensity physical exercise (brisk walking to slow jogging) on platelet aggregation in a population-based sample of middle-aged, overweight, mildly hypertensive men in eastern Finland. In this controlled study, we evaluated the net effect of exercise on platelet aggregation by studying changes in optical density and ATP release in platelet-rich plasma. A significant inhibition of secondary platelet aggregation from 27% to 36% was observed in the men taking regular exercise. These findings give new insight into the possible protective effects of exercise against the risk of ischemic heart disease.

Although blood cardioplegia preserves perioperative ventricular function better than crystalloid cardioplegia, late results are uncertain. Nuclear ventriculograms were used to assess ventricular function in 47 patients undergoing coronary bypass surgery who were randomly assigned to receive blood (23 patients) or crystalloid cardioplegia (24 patients). Data were acquired at rest and during maximal exercise (bicycle ergometer) 1 month before surgery (PRE), 5 months after surgery (POST), and perioperatively at rest 3 to 5 hr after operation (PERI). Perioperatively, blood cardioplegia decreased ischemic injury (less elevation in creatine kinase-MB fraction and aspartate aminotransferase; p less than .05), preserved ventricular performance (lower stroke work index at higher left ventricular end-diastolic volume index after crystalloid than blood cardioplegia; p = .02 by analysis of covariance [ANOCOVA]) and preserved systolic function (higher left ventricular end-systolic volume index [LVESVI] at similar systolic blood pressure after crystalloid than blood cardioplegia; p = .02 by ANOCOVA). Postoperatively, resting ventricular performance and systolic function were not different with blood and crystalloid cardioplegia and were similar to preoperative measurements. Postoperatively, the response to exercise was similar between the two groups and was improved compared with that at PRE. Postoperative systolic function at exercise was similar between the two groups but was better than that at PRE (higher systolic blood pressure at similar LVESVI; p = .01 by ANOCOVA). The type of cardioplegic solution influenced perioperative but not late postoperative function after elective coronary artery bypass surgery.

Combined proximal left anterior descending and proximal left circumflex, or "left main equivalent" (LMEQ), disease defines a prognostic angiographic high-risk patient population. We assessed the effect of coronary bypass surgery compared with medical therapy in 903 patients with LMEQ disease by stratified life table and Cox regression analysis. The 5 year survival rates of the 639 and 264 patients who received surgical vs medical therapy was 85% vs 55%, respectively (p less than .001). Analysis of patient subsets stratified by age, angina class, right coronary disease, and ejection fraction revealed a significant survival benefit for surgically treated patients in most strata. Cox regression analysis revealed improved survival for surgically treated patients after adjustment for important baseline variables known to influence prognosis. Surgically treated patients had significantly less angina and need for antianginal drugs compared with the medically treated group. When the Coronary Artery Surgery Study randomized and randomizable LMEQ patients were analyzed, coronary bypass surgery improved 5 year survival when preoperative ejection fraction was under 0.50 but not when ejection fraction was 0.50 or higher. Thus coronary bypass surgery prolongs and improves quality of life (as defined by angina status and need for antianginal drugs) in most patients with LMEQ disease but does not appear to improve 5 year survival in a small subset of LMEQ patients who are asymptomatic after myocardial infarction or who have mild chronic stable angina and are under age 65 with well-preserved left ventricular function.

Exercise conditioning involves adaptations in the heart, peripheral circulation, and trained skeletal muscle that result in improved exercise capacity. Since the specific influence of beta-adrenergic stimulation on these various adaptations has not been clear, we studied the effect of beta 1-selective and nonselective beta-adrenergic blockade on the exercise conditioning response of 24 healthy, sedentary men after an intensive 6 week aerobic training program. Subjects randomly assigned to receive placebo, 50 mg bid atenolol, or 40 mg bid nadolol were tested before and after training both on and off drugs. Comparable reductions in maximal exercise heart rate occurred with atenolol and nadolol, indicating equivalent beta 1-adrenergic blockade. Vascular beta 2-adrenergic selectivity was maintained with atenolol as determined by calf plethysmography during intravenous infusion of epinephrine. All subjects trained at greater than 85% of maximal heart rate and 80% of VO2 max determined on drug. VO2 max increased after training 16 +/- 2% (p less than .05) in the placebo group and 6 +/- 2% (p less than .05) in the atenolol group, while there was no change in the nadolol group. At maximal exercise, subjects receiving placebo increased their exercise duration and oxygen pulse significantly greater than those receiving atenolol or nadolol. During submaximal exercise there were reductions in heart rate and heart rate-blood pressure product in all three groups, but these reductions were greater with placebo than with either drug. Leg blood flow during submaximal exercise decreased 24 +/- 2% (p less than .01) in the placebo group but was unchanged in the atenolol and nadolol groups. Lactates in arterialized blood during submaximal exercise were reduced equivalently in all three groups after training. Capillary/fiber ratio in vastus lateralis muscle biopsy specimens increased 31 +/- 6% in the placebo group and 21 +/- 6% in the atenolol group (both p less than .05) and tended to increase in the nadolol group. Succinic dehydrogenase and cytochrome oxidase activities in muscle biopsy specimens increased equivalently in all three groups, especially during submaximal exercise, these changes were less marked than that with placebo. While beta-adrenergic blockade attenuated the exercise conditioning response, skeletal muscle adaptations including increases in oxidative enzymes, capillary supply, and decreases in exercise blood lactates were unaffected. Cardiac and peripheral vascular adaptations do appear to be affected by beta-adrenergic blockade during training. Cardioselectivity does not seem to be important in modifying these effects.

To determine whether alteration of intrinsic myocardial stiffness is responsible for the reduction of left ventricular filling pressure and volume by nifedipine in patients with impaired baseline ventricular function, we evaluated the hemodynamic responses in 32 patients undergoing diagnostic cardiac catheterization. Micromanometric pressure and ventriculographic dimensional data were acquired before and 30 min after randomly assigned administration of nifedipine (20 mg sublingual) or placebo. A mathematical model requiring no assumptions about the stress-radius relationship or direct measurement of strain was used. No hemodynamic variables were changed after placebo. Left ventricular end-diastolic volume and pressure declined and cardiac output increased after nifedipine, particularly in subjects with impaired ventricular performance. Despite these salutary effects, intrinsic myocardial stiffness, elastic stiffness at a common level of stress, chamber stiffness, and rate of isovolumic relaxation were unchanged after nifedipine, even in patients with abnormal baseline ventricular function. The potent peripheral arteriodilator effect of nifedipine, rather than any direct myocardial or ventricular effects, appears to be responsible for the improved systolic and diastolic performance.

From 1975 to 1979, 540 patients undergoing valve replacement were entered into a randomized trial and received either a Björk-Shiley (273 patients) or a porcine heterograft prosthesis (initially a Hancock valve [107 patients] and later a Carpentier-Edwards prosthesis [160 patients]). Two hundred and sixty-two patients required mitral valve replacement, 210 required aortic valve replacement, 60 required mitral and aortic valve replacement, and eight also required associated tricuspid valve replacement (six mitral valve replacement; two mitral plus aortic valve replacement). Analysis of 34 preoperative and operative variables showed the treatment groups to be well randomized. In-hospital mortality was not significantly different among patients receiving the three prostheses for aortic valve replacement (7.6% overall) and mitral plus aortic valve replacement (10% overall), but there was a higher in-hospital mortality for patients undergoing mitral valve replacement with the Carpentier-Edwards prosthesis (15.5% compared with 8.8% overall; p = .03). This difference could not be explained on the basis of any preoperative or operative variable. Median follow-up was 5.6 (range 2.8 to 8.3) years. Actuarial survival after mitral valve replacement was 56.7 +/- 7.0% at 7 years, that after aortic valve replacement was 69.6 +/- 9.6% at 7 years, and that after mitral plus aortic valve replacement was 62.5 +/- 20.0% at 7 years. There was no significant difference in actuarial survival of patients receiving the three prostheses within the mitral, aortic, and mitral plus aortic valve replacement groups, nor was there a difference when these groups were amalgamated. Thirty-seven patients required reoperation for valve failure (15 with Björk-Shiley, 12 with Hancock, and 10 with Carpentier-Edwards valves; p = NS) and 11 died at reoperation (four with Björk-Shiley, four with Hancock, and three with Carpentier-Edwards valves; overall operative mortality 29.7%). Up to 7 years after surgery, there was no significant difference in the incidence of thromboembolism in patients with different prostheses undergoing mitral or aortic valve replacement. There were too few patients undergoing mitral plus aortic valve replacement for meaningful comparison. There was no significant beneficial effect of anticoagulants in patients undergoing mitral or aortic valve replacement with porcine prostheses, but patients were not randomly allocated to anticoagulant treatment. All patients with Björk-Shiley prostheses received anticoagulants.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of abrupt withdrawal or continuation of beta-blockade therapy during acute myocardial infarction were evaluated in 326 patients participating in the Multicenter Investigation of the Limitation of Infarct Size (MILIS). Thirty-nine patients previously receiving a beta-blocker and randomly selected for withdrawal of beta-blockers and placebo treatment during infarction (group 1) were compared with 272 patients previously untreated with beta-blockers who were also randomly assigned to placebo therapy (group 2). There were no significant differences between the two groups in MB creatine kinase isoenzyme (15.8 +/- 10.9 vs 18.2 +/- 14.4 g-eq/m2, respectively) estimates of infarct size, radionuclide-determined left ventricular ejection fractions within 18 hr of infarction (0.44 +/- 0.15 vs 0.47 +/- 0.16) or 10 days later (0.42 +/- 0.14 vs 0.47 +/- 0.16), creatine kinase-determined incidence of infarct extension (13% vs 6%), congestive heart failure (43% vs 37%), nonfatal ventricular fibrillation (5% vs 7%), or in-hospital mortality (13% vs 9%). Patients in group 1 had more recurrent ischemic chest pain (p = .002) within the first 24 hr after infarction, but not thereafter. However, this did not appear to be related to a rebound increase in systolic blood pressure, heart rate, or double product. In a separate analysis, 20 propranolol-eligible group 1 patients randomly selected for withdrawal of beta-blockade (group 3) were compared with 15 patients randomly selected for continuation of prior beta-blockade therapy (group 4). This comparison yielded similar results. These data indicate that the beta-blockade withdrawal phenomenon is not a major clinical problem in patients with acute myocardial infarction. beta-Blockade therapy can be discontinued abruptly during acute myocardial infarction if clinically indicated.